Epidemiologic, immunologic, and pathologic evidence has suggested that, in a significant number of cases, schizophrenia may be related to infection with or activation of a viral disease of the brain. To pursue this possibility, we previously undertook immunocytochemical and in situ hybridization studies of brain in which we sought evidence of specific viral antigens or genomes. With rare exceptions, these studies did not disclose viral antigens. Intracerebral inoculation of schizophrenic brains into guinea pigs and non-human primates also yielded negative results. Two new approaches have since been undertaken: (1) Co- cultivation of schizophrenic or control CSF lymphocytes with human neuroblastoma cells (SH-EP), and (2) Intracerebral inoculation of control or schizophrenic lymphocytes in newborn mice. The best study demonstrated growth to a higher density of SH-EP cells treated with CSF cells (freshly drawn) from 10 of 12 chronic schizophrenic patients from the NIMH unit at St. Elizabeths' Hospital. In an attempt at replication, a spundown aliquot of CSF from 12 patients with acute or schizophrenia, and from 13 age-matched neurologic controls from the Oregon Health Sciences University in Portland, Oregon and cooperating hospitals, were cultured with SH-EP human neuroblastoma cells. In contrast to the SEH material, all of the Oregon cultures, treated with schizophrenic and with control CSF, grew to the same high density. We attributed this to changes in culture medium and environment, and launched a 3d study with patients from SEH and schizophrenic twins. Five schizophrenic patients and O controls have transformed SH-EP cells. Current work is focused on cloning and sequencing the nucleic acid responsible for the transformation. We are also repeating the original study of CSF on a new group of Saint Elizabeths' patients and controls. In the spring of 1988, we inoculated frozen CSF from acute and chronic schizophrenic patients (n=14) and controls (n=13) intracranially in newly born mice (n=107). Systematic behavior tests were done on these animals at two months of age. Animals were sacrificed if sick or at one year after inoculation if no illness developed. No significant changes were found in brains of schizophrenic compared to control mice, with the exception of larger ventricles in mice injected with fresh, but not frozen CSF.